Improved biodistribution of 125I-labeled anti-Tac disulfide- stabilized Fv fragment by blocking its binding to the α subunit of the interleukin 2 receptor in the circulation with preinjected humanized anti- Tac IgG

Hisataka Kobayashi, Tae M. Yoo, Debra Drumm, Meyoung-Kon Kim, Bao Fu Sun, Nhat Le, Keith O. Webber, Ira Pastan, Thomas A. Waldmann, Chang H. Paik, Jorge A. Carrasquillo

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Abstract

Animal studies using radiolabeled anti-Tac disulfide-stabilized Fv (dsFv) monoclonal antibody have shown formation of complexes in serum with the soluble α subunit of the interleukin 2 receptor α (sIL-2Rα). In this study, we improved the targeting of 125I-labeled anti-Tac dsFv to receptor-positive tumors in the presence of circulating receptor by preinjecting unlabeled humanized anti-Tac IgG antibody (HuTac IgG). We used mice bearing SP2/Tac tumor xenografts that express the IL-2Rα. A positive correlation was seen between tumor size and the concentration of circulating receptor. Tumor-bearing mice were injected with 125I-labeled anti-Tac dsFv (400 ng), either alone or 15 min after injection of HuTac IgG. The 125I- labeled anti-Tac dsFv formed high molecular weight complexes with the sIL- 2Rα. The fraction of the dsFv present in the complexes increased as tumor size increased (greater sIL-2Rα levels). The fractions of dsFv in the complexes were 9.9- to 11.6-fold higher when sIL-2Rα was not blocked with preinjected HuTac IgG. The administration of a 12-fold molar excess of HuTac IgG over sIL-2Rα resulted in >80% of the 125I activity present as the dsFv rather than in the complexes. Furthermore, the biodistribution of 125I-labeled anti-Tac dsFv was improved by blocking its binding to sIL- 2Rα by preinjecting HuTac IgG. Specifically, in the preinjected group, at 15 min postinjection, the 125I-labeled anti-Tac dsFv levels in tumor increased to 10.8% compared to 5.6% injected dose per gram in the non- preinjected group. In summary, our studies showed that preinjection of HuTac IgG can block the formation of complexes of circulating sIL-2Rα and 125I- labeled anti-Tac dsFv. This blockade is associated with faster blood clearance, higher tumor uptake, and greater tumor:nontumor ratios of the radiolabeled antibody fragment.

Original languageEnglish
Pages (from-to)1955-1961
Number of pages7
JournalCancer Research
Volume57
Issue number10
Publication statusPublished - 1997 May 15
Externally publishedYes

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Immunoglobulin Variable Region
Interleukin-2 Receptors
Disulfides
Neoplasms
Immunoglobulin G
Antibodies
anti-IgG
Immunoglobulin Fragments
Heterografts
Molecular Weight
Monoclonal Antibodies

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Improved biodistribution of 125I-labeled anti-Tac disulfide- stabilized Fv fragment by blocking its binding to the α subunit of the interleukin 2 receptor in the circulation with preinjected humanized anti- Tac IgG. / Kobayashi, Hisataka; Yoo, Tae M.; Drumm, Debra; Kim, Meyoung-Kon; Sun, Bao Fu; Le, Nhat; Webber, Keith O.; Pastan, Ira; Waldmann, Thomas A.; Paik, Chang H.; Carrasquillo, Jorge A.

In: Cancer Research, Vol. 57, No. 10, 15.05.1997, p. 1955-1961.

Research output: Contribution to journalArticle

Kobayashi, Hisataka ; Yoo, Tae M. ; Drumm, Debra ; Kim, Meyoung-Kon ; Sun, Bao Fu ; Le, Nhat ; Webber, Keith O. ; Pastan, Ira ; Waldmann, Thomas A. ; Paik, Chang H. ; Carrasquillo, Jorge A. / Improved biodistribution of 125I-labeled anti-Tac disulfide- stabilized Fv fragment by blocking its binding to the α subunit of the interleukin 2 receptor in the circulation with preinjected humanized anti- Tac IgG. In: Cancer Research. 1997 ; Vol. 57, No. 10. pp. 1955-1961.
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abstract = "Animal studies using radiolabeled anti-Tac disulfide-stabilized Fv (dsFv) monoclonal antibody have shown formation of complexes in serum with the soluble α subunit of the interleukin 2 receptor α (sIL-2Rα). In this study, we improved the targeting of 125I-labeled anti-Tac dsFv to receptor-positive tumors in the presence of circulating receptor by preinjecting unlabeled humanized anti-Tac IgG antibody (HuTac IgG). We used mice bearing SP2/Tac tumor xenografts that express the IL-2Rα. A positive correlation was seen between tumor size and the concentration of circulating receptor. Tumor-bearing mice were injected with 125I-labeled anti-Tac dsFv (400 ng), either alone or 15 min after injection of HuTac IgG. The 125I- labeled anti-Tac dsFv formed high molecular weight complexes with the sIL- 2Rα. The fraction of the dsFv present in the complexes increased as tumor size increased (greater sIL-2Rα levels). The fractions of dsFv in the complexes were 9.9- to 11.6-fold higher when sIL-2Rα was not blocked with preinjected HuTac IgG. The administration of a 12-fold molar excess of HuTac IgG over sIL-2Rα resulted in >80{\%} of the 125I activity present as the dsFv rather than in the complexes. Furthermore, the biodistribution of 125I-labeled anti-Tac dsFv was improved by blocking its binding to sIL- 2Rα by preinjecting HuTac IgG. Specifically, in the preinjected group, at 15 min postinjection, the 125I-labeled anti-Tac dsFv levels in tumor increased to 10.8{\%} compared to 5.6{\%} injected dose per gram in the non- preinjected group. In summary, our studies showed that preinjection of HuTac IgG can block the formation of complexes of circulating sIL-2Rα and 125I- labeled anti-Tac dsFv. This blockade is associated with faster blood clearance, higher tumor uptake, and greater tumor:nontumor ratios of the radiolabeled antibody fragment.",
author = "Hisataka Kobayashi and Yoo, {Tae M.} and Debra Drumm and Meyoung-Kon Kim and Sun, {Bao Fu} and Nhat Le and Webber, {Keith O.} and Ira Pastan and Waldmann, {Thomas A.} and Paik, {Chang H.} and Carrasquillo, {Jorge A.}",
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AU - Kobayashi, Hisataka

AU - Yoo, Tae M.

AU - Drumm, Debra

AU - Kim, Meyoung-Kon

AU - Sun, Bao Fu

AU - Le, Nhat

AU - Webber, Keith O.

AU - Pastan, Ira

AU - Waldmann, Thomas A.

AU - Paik, Chang H.

AU - Carrasquillo, Jorge A.

PY - 1997/5/15

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N2 - Animal studies using radiolabeled anti-Tac disulfide-stabilized Fv (dsFv) monoclonal antibody have shown formation of complexes in serum with the soluble α subunit of the interleukin 2 receptor α (sIL-2Rα). In this study, we improved the targeting of 125I-labeled anti-Tac dsFv to receptor-positive tumors in the presence of circulating receptor by preinjecting unlabeled humanized anti-Tac IgG antibody (HuTac IgG). We used mice bearing SP2/Tac tumor xenografts that express the IL-2Rα. A positive correlation was seen between tumor size and the concentration of circulating receptor. Tumor-bearing mice were injected with 125I-labeled anti-Tac dsFv (400 ng), either alone or 15 min after injection of HuTac IgG. The 125I- labeled anti-Tac dsFv formed high molecular weight complexes with the sIL- 2Rα. The fraction of the dsFv present in the complexes increased as tumor size increased (greater sIL-2Rα levels). The fractions of dsFv in the complexes were 9.9- to 11.6-fold higher when sIL-2Rα was not blocked with preinjected HuTac IgG. The administration of a 12-fold molar excess of HuTac IgG over sIL-2Rα resulted in >80% of the 125I activity present as the dsFv rather than in the complexes. Furthermore, the biodistribution of 125I-labeled anti-Tac dsFv was improved by blocking its binding to sIL- 2Rα by preinjecting HuTac IgG. Specifically, in the preinjected group, at 15 min postinjection, the 125I-labeled anti-Tac dsFv levels in tumor increased to 10.8% compared to 5.6% injected dose per gram in the non- preinjected group. In summary, our studies showed that preinjection of HuTac IgG can block the formation of complexes of circulating sIL-2Rα and 125I- labeled anti-Tac dsFv. This blockade is associated with faster blood clearance, higher tumor uptake, and greater tumor:nontumor ratios of the radiolabeled antibody fragment.

AB - Animal studies using radiolabeled anti-Tac disulfide-stabilized Fv (dsFv) monoclonal antibody have shown formation of complexes in serum with the soluble α subunit of the interleukin 2 receptor α (sIL-2Rα). In this study, we improved the targeting of 125I-labeled anti-Tac dsFv to receptor-positive tumors in the presence of circulating receptor by preinjecting unlabeled humanized anti-Tac IgG antibody (HuTac IgG). We used mice bearing SP2/Tac tumor xenografts that express the IL-2Rα. A positive correlation was seen between tumor size and the concentration of circulating receptor. Tumor-bearing mice were injected with 125I-labeled anti-Tac dsFv (400 ng), either alone or 15 min after injection of HuTac IgG. The 125I- labeled anti-Tac dsFv formed high molecular weight complexes with the sIL- 2Rα. The fraction of the dsFv present in the complexes increased as tumor size increased (greater sIL-2Rα levels). The fractions of dsFv in the complexes were 9.9- to 11.6-fold higher when sIL-2Rα was not blocked with preinjected HuTac IgG. The administration of a 12-fold molar excess of HuTac IgG over sIL-2Rα resulted in >80% of the 125I activity present as the dsFv rather than in the complexes. Furthermore, the biodistribution of 125I-labeled anti-Tac dsFv was improved by blocking its binding to sIL- 2Rα by preinjecting HuTac IgG. Specifically, in the preinjected group, at 15 min postinjection, the 125I-labeled anti-Tac dsFv levels in tumor increased to 10.8% compared to 5.6% injected dose per gram in the non- preinjected group. In summary, our studies showed that preinjection of HuTac IgG can block the formation of complexes of circulating sIL-2Rα and 125I- labeled anti-Tac dsFv. This blockade is associated with faster blood clearance, higher tumor uptake, and greater tumor:nontumor ratios of the radiolabeled antibody fragment.

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